Methods and compositions particularly for treatment of attention deficit disorder

ABSTRACT

There is described, inter alia, a coated bead comprising: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of an active pharmaceutical ingredient comprising a central nervous system stimulant; and (c) a second layer coated over the first layer, the second layer being present in an amount sufficient to substantially delay release of the active pharmaceutical ingredient in the first layer until after the coated bead reaches a distal intestine portion of a subject to whom the coated bead is administered; and (d) the third layer coated over the second layer, the third layer comprising a second amount of the active pharmaceutical ingredient, the third layer being configured to permit substantially immediate release of the active pharmaceutical ingredient comprised therein. Embodiments related to a solid oral pharmaceutical composition are also described.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to methods and compositions, particularlyfor treatment of attention deficit disorder.

Description of the Prior Art

Sustained release dosage forms are important in the search for improvedtherapy, both through improved patient compliance and decreasedincidences of adverse drug reactions.

It is the intent of sustained release formulations to provide a longerperiod of pharmacologic action after administration than is ordinarilyobtained after administration of immediate release dosage forms.Sustained release compositions may be used to delay absorption of amedicament until it has reached certain portions of the alimentarytract, and maintain a desired concentration of the medicament in theblood stream for a longer duration than would occur if conventionalrapid release dosage forms are administered. Such longer periods ofresponse provide for many therapeutic benefits that are not achievedwith corresponding short acting, immediate release preparations. Thus,therapy may be continued without interrupting the sleep of the patient,which is of special importance, for example, when treating a patient formoderate to severe pain (e.g., a post-surgery patient, a cancer patient,etc.), or for those patients who experience migraine headaches onawakening, as well as for the debilitated patient for whom sleep isessential. A further general advantage of longer acting drugpreparations is improved patient compliance resulting from the avoidanceof missed doses through patient forgetfulness.

Unless conventional rapid acting drug therapy is carefully administeredat frequent intervals to maintain effective steady state blood levels ofthe drug, peaks and valleys in the blood level of the active drug occurdue to rapid absorption, systemic excretion of the compound and throughmetabolic inactivation, thereby producing special problems inmaintenance therapy of the patient.

In view of this, it is considered a goal of many skilled in the art thata controlled release dosage form will ideally provide therapeuticconcentration of the drug in blood that is maintained throughout thedosing interval with a reduction in the peak/trough concentration ratio.Central to the development process are the many variables that influencethe in vivo release and subsequent absorption of the active ingredientsfrom the gastrointestinal tract.

It is known in the pharmaceutical art to prepare compositions whichprovide for sustained release of pharmacologically active substancescontained in the compositions after oral administration to humans andanimals. Sustained release formulations known in the art includespecially coated pellets, coated tablets and capsules, and ion exchangeresins, wherein the slow release of the active medicament is broughtabout through selective breakdown of the coating of the preparation orthrough compounding with a special matrix to affect the release of adrug. Some sustained release formulations provide for related sequentialrelease of a single dose of an active compound at predetermined periodsafter administration.

Thus, sustained release dosage forms are important in the search forimproved therapy, both through improved patient compliance and decreasedincidences of adverse drug reactions.

While controlled and/or sustained release compositions have constituteda definite advance in the art, improvements in these compositions havebeen sought, particularly for preparations available for conditions suchas Attention Deficit Hyperactivity Disorder (ADHD), diabetes etc.

Attention Deficit Disorders are the most common psychiatric disorders inchildren (Campbell et al. 1992) with reported rates ranging from 4% to9% (Aman et al. 1983).

Attention Deficit Disorder (ADD) is characterized by inattention andimpulsivity and may be present with hyperactivity (ADHD) (Shaywitz etal. 1984). Other characteristics may include aggressiveness, stealing,lying, truancy, setting fires, running away, explosiveness, cognitiveand learning problems as well as poor social skills (Campbell et al.1992). It is four to five times more frequent in boys than girls(Campbell et al. 1992).

Stimulant medication, such as amphetamines, have been shown to be themost effective agents in the treatment of children with disorders ofactivity modulation and attention regulation and result in significantimprovement in 70 to 80 percent of affected children (Shaywitz et al.1984). Positive effects of stimulants have been documented in a varietyof areas including behavioral, social, perceptual performance, motoractivity, impulse control, attention regulation and cognitiveperformance (Barkley 1977, Kavale 1983, Offenbacher et al. 1983,Rosenthal et al 1978).

Long thought of as a childhood disorder, ADHD is now known to persistinto adolescence and adulthood (Practice Parameter for the Use ofStimulant Medications in the treatment of Children, Adolescents, andAdults. J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 41:2 SUPPLEMENT,FEBRUARY 2002)

Methylphenidate [dl-threo-methyl-2-phenyl-2-(2-piperidyl)acetate] is thepsycho-stimulant used most frequently in the treatment of hyperactivityand attention deficit disorder. It appears to have a higher incidence ofpositive effects and a lower incidence of adverse effects than otherpsychostimulants. The efficacy of methylphenidate (“MPH”) in improvingattention and behavioral symptoms has been supported by many studies.

Immediate release methylphenidate preparations, because of their shorthalf-life, require frequent administration at short intervals to ensureadequate treatment throughout a child's school day, adolescence's schoolday (high school, college, university) and adult working day. The rapidonset and offset of immediate release methylphenidate preparations meansthat a medicated person with attention deficit disorder will bemaximally affected only for relatively brief periods during the day. Dueto its short half-life, it has been known to administer MPH given twiceper day, usually once after breakfast and once during the day, an eventthat some children and some school personnel apparently avoid, resultingin poor compliance with prescribed regimens (Brown et al., 1985;Firestone 1982).

Compliance is a major problem for children, adolescences and adults.Poor compliance in taking medication may explain, in part, the variableand conflicting results reported in many studies of the effect ofmedication on improving the behavior of hyperactive children,adolescents and adults. These limitations of immediate releasemethylphenidate led to interest in products with longer effectiveperiods of action.

Thus, much of the prior art has focussed on development of formulationsfor treatment of ADHD with a focus on administration to children andimproving patient compliance in the patient population. This has led tocommercialization of a number of sustained release formulations ofmethylphenidate—e.g., Ritalin SR™, Concerta™ and Biphentin™.

Duration of efficacy with long-acting methylphenidate formulations wasmaintained from one hour to 12 hours post-dosing for osmoticallycontrolled-release oral delivery systems (four trials), 1.5 hours to 7.5hours for methylphenidate extended release in one trial, one hour to 12hours post-dosing for methylphenidate spheroidal oral drug absorptionsystems (two trials) and 30 minutes to 12 hours post-dosing fordexmethylphenidate extended release (five trials). Most long-actingstimulants conferred benefits on ADHD symptoms in patients across theage spectrum for up to 12 hours after a single morning dose as measuredby the permanent product measure of performance mathematics test(PERMP). Formulations may differ in time to peak effect and maintenanceof effect as well as magnitude of effect at different time points duringthe day (Brams M, Moon E, Pucci M, Lopez F A. Duration of effect of orallong-acting stimulant medications for ADHD throughout the day. Curr MedRes Opin. 2010 August; 26(8):1809-25. doi:10.1185/03007995.2010.488553).

Despite the advances in the art, there is still room for improvement.

First, some or all of the commercially available sustained releaseformulations of methylphenidate do not have, in combination, a rapidonset of action and a duration of action that exceeds 12 hours. Theprovision of a sustained release formulation having this combination offeatures would be highly desirable for adolescents or adults whose dailyactivities require them to have a rapid onset of therapeutic effect andduration of action that lasts at least 14 hours to get them through theday and will into the evening without the need of another dose of themedication.

Second, some or all of the commercially available sustained releaseformulations of methylphenidate are susceptible to premature release ofthe active ingredient in a gastric environment that contains alcohol(e.g., ethanol). This can be a significant problem if the subject takingthe formulation is an alcohol abuser.

This, it would be highly desirable to have a pharmaceutical compositionthat obviates or mitigates one or both of these problems in the priorart.

SUMMARY OF THE INVENTION

It is an object of the present invention to obviate or mitigate at leastone of the above-mentioned disadvantages of the prior art.

It is another object of the present invention to provide a novel coatedbead.

It is another object of the present invention to provide a novel solidoral pharmaceutical composition.

Accordingly, in one of its aspects, the present invention provides acoated bead comprising:

(a) a granule;

(b) a first layer coated over the granule, the first layer comprising afirst amount of an active pharmaceutical ingredient comprising a centralnervous system stimulant;

(c) a second layer coated over the first layer, the second layer beingpresent in an amount sufficient to substantially delay release of theactive pharmaceutical ingredient in the first layer until after thecoated bead reaches a distal intestine portion of a subject to whom thecoated bead is administered; and

(d) a third layer coated over the second layer, the third layercomprising a second amount of the active pharmaceutical ingredient, thethird layer being configured to permit substantially immediate releaseof the active pharmaceutical ingredient comprised therein.

In another of its aspects, the present invention provides a an oralsolid pharmaceutical composition comprising a first plurality of coatedbeads and a second plurality of coated beads, wherein:

each coated bead in the first plurality of coated beads comprising: afirst granule and a first layer coated over the first granule, the firstlayer comprising an active pharmaceutical ingredient comprising acentral nervous system stimulant, the first plurality of coated beadsbeing configured to provide substantially immediate release of theactive pharmaceutical ingredient; and

each coated bead in the second plurality of coated beads comprising: asecond granule; a first layer coated over the granule, the first layercomprising an active pharmaceutical ingredient comprising a centralnervous system stimulant; and a second layer coated over the firstlayer, the second layer being present in an amount sufficient tosubstantially delay release of the active pharmaceutical ingredient inthe first layer until after the coated bead reaches a distal intestineportion of a subject to whom the coated bead is administered, the coatedbead being substantially free of an outer layer configured to providesubstantially immediate release of the active pharmaceutical ingredient.

In yet another of its aspects, the present invention provides an oralsolid pharmaceutical composition comprising a first plurality of coatedbeads, a second plurality of coated beads and a third plurality ofcoated bead, wherein:

each coated bead in the first plurality of coated beads comprising: afirst granule and a first layer coated over the first granule, the firstlayer comprising an active pharmaceutical ingredient comprising acentral nervous system stimulant, the first plurality of coated beadsbeing configured to provide substantially immediate release of theactive pharmaceutical ingredient;

each coated bead in the second plurality of coated beads comprising: asecond granule; a first layer coated over the granule, the first layercomprising an active pharmaceutical ingredient comprising a centralnervous system stimulant; and a second layer coated over the firstlayer, the second layer being present in an amount sufficient tosubstantially delay release of the active pharmaceutical ingredient inthe first layer; and each coated bead in the third plurality of coatedbeads comprising: a third granule; a first layer coated over thegranule, the first layer comprising an active pharmaceutical ingredientcomprising a central nervous system stimulant, a second layer coatedover the first layer, the second layer being present in an amountsufficient to substantially delay release of the active pharmaceuticalingredient in the first layer until after the coated bead reaches adistal intestine portion of a subject to whom the coated bead isadministered.

In yet another of its aspects, the present invention provides a coatedbead comprising:

(a) a granule;

(b) an inner layer coated over the granule, the inner layer comprisingan active pharmaceutical ingredient comprising a central nervous systemstimulant; and

(c) an outer delayed release layer coated over inner layer which issubstantially free of a salt of alginic acid;

wherein release of the active pharmaceutical ingredient is not more than20% when measured under in vitro conditions with stirring at 100 rpm atpH 1.2 for 2 hours in 900 mL of a medium comprising up to about 35% v/vethanol

In yet another of its aspects, the present invention provides a coatedbead comprising:

(a) a granule;

(b) an inner layer coated over the granule, the inner layer comprisingan active pharmaceutical ingredient comprising a central nervous systemstimulant; and

(c) an outer delayed release layer coated over inner layer, the outerdelayed release coating comprises an anionic copolymer based on methylacrylate, methyl methacrylate and methacrylic acid with the proviso thatthe outer delayed release layer is substantially free of a salt ofalginic acid, the outer delayed release layer being present at anaverage thickeness in the range of of from about 5 μm to about 50 μm.

In yet another of its aspects, the present invention provides a coatedbead comprising:

(a) a granule comprising a first amount of an active pharmaceuticalingredient comprising a central nervous system stimulant (e.g., thegranule can comprise a granule substrate in admixture with the activepharmaceutical ingredient or the active pharmaceutical ingredient couldbe coated over the granule substrate); and

(b) a first layer coated over the granule, the first layer being presentin an amount sufficient to substantially delay release of the activepharmaceutical ingredient in the first layer until after the coated beadreaches a distal intestine portion of a subject to whom the coated beadis administered; and

(c) a second layer coated over the first layer, the second layercomprising a second amount of the active pharmaceutical ingredient, thesecond layer being configured to permit substantially immediate releaseof the active pharmaceutical ingredient comprised therein.

Throughout this specification, the term “coated over” (or the functionalequivalent thereof) is used to describe a first layer of materialdisposed exteriorly with respect to a second layer of material. Itshould be clearly understood that, in such a case, the first layer layerof material may be directly coated over (i.e., in contacting relationwith) the second layer of material or indirectly coated over (i.e., innon-contacting relation with) the second layer of material. An exampleof the “indirectly coated over” would be when the first layer ofmaterial and the second layer of material has disposed between them oneor more intermediate layers of material. The point is the term “coatedover” (or the functional equivalent thereof), when used on its ownencompasses both “directly coated over” and “indirectly coated over”described above.

The present inventors have developed a novel coated bead and a novelpharmaceutical composition which are believed to obviate or mitigate oneor both of the above-mentioned disadvantages described above withreference to some or all of the commercially available sustained releaseformulations of methylphenidate. The present coated bead andpharmaceutical composition are believed to be highly advantageous inthat they have a rapid on set of action (e.g., approximately 1 hourafter administration) and a long duration of action (e.g., approximately16 hours or more) after reaching steady state in the subject. While notwishing to be bound by any particular theory or mode of action, it isbelieved that the long duration of action results in a blood plasmaconcentration of the active ingredient at 24 hours after administrationwhich allows for a rapid onset of action when another dose of the activeingredient is taken—i.e., there appears to be a baseline blood plasmaconcentration of the active ingredient when it is time to take asubsequent dose to allow for a rapid onset of action of that subsequentdose.

The present coated bead and pharmaceutical composition are believed toaddress a limitation of some or all current commercially availablelong-acting methylphenidate formulations which are not reported toprovide and maintain duration of action beyond 12 hours. The presentcoated bead and pharmaceutical composition are also believed to addressthe limitation with long-acting lisdexamfetamine dimesylate that isreported to last up to 14 hours but do not have a rapid onset of action.These two characteristics (rapid onset of action and long duration ofaction) of the present coated bead and pharmaceutical composition arebelieved to address a significant limitation for adolescences or adultswhose daily activities require them to have a rapid onset of therapeuticeffect and duration of action that lasts at least 14 hours to get themthrough the day and will into the evening without the need of anotherdose of the medication.

In one preferred embodiment, the present coated bead and pharmaceuticalcomposition are characterized by having a resistance release of theactive ingredient in an aqueous composition comprising up to about 35%by volume of an alcohol (e.g., ethanol)—i.e., release of the activepharmaceutical ingredient is not more than 20% when measured under invitro conditions with stirring at 100 rpm at pH 1.2 for 2 hours in 900mL of a medium comprising up to about 35% v/v ethanol. This resistanceto alcohol-related release of the active pharmaceutical ingredient canbe achieved without the need to use coating layer comprising one or moresalts of aglinic acid thereby simplifying manufacturing costs and thelike.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will be described with reference tothe accompanying drawings, wherein like reference numerals denote likeparts, and in which:

FIGS. 1-10 illustrate results on testing done on formulations producedin the examples described below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The coated bead and solid oral pharmaceutical compositions of thepresent invention include a central nervous system stimulant which canbe generally defined as a chemical entity that affects the dopamine ornorepinephrine neural pathways. Preferred pharmaceutically activeingredients include, but are not limited to amphetamine,dextroamphetamine, the active isomers of amphetamines and amphetaminesalts including salts of dextroamphetamine, methylphenidate and itsactive salts, or combinations thereof, all of which can be used asracemic mixtures or pure isomers such as d-threo methylphenidate, or aprodrug or pharmaceutical salt, or mixed pharmaceutical salts of anythereof alone or in combination. The disclosed coated bead and solidoral pharmaceutical compositions can also include a prodrug, includingbut not limited to amino acid conjugated active ingredients such as1-lysine-d-amphetamine.

Conditions or disorders that can be treated using the present coatedbead or solid oral pharmaceutical compositions include, but are notlimited to attention deficit disorder (ADD), attention deficithyperactivity disorder (ADHD), excessive daytime sleepiness, majordepressive disorder, bipolar depression, negative symptoms inschizophrenia, chronic fatigue, fatigue associated with chemotherapy orbinge eating disorder. Attention deficit disorders are characterized byhyperactive, impulsive or inattentive symptoms that cause impairment insocial, academic, or occupational functioning, and are often present intwo or more settings, school (or work) and at home, for example. For theInattentive Type, at least 6 (5 for adults ≥18 years of age) of thefollowing symptoms have persisted for at least 6 months: lack ofattention to details/careless mistakes; lack of sustained attention;poor listener; failure to follow through on tasks; poor organization;avoids tasks requiring sustained mental effort; loses things; easilydistracted; and forgetful. For the Hyperactive-Impulsive Type, at least6 (5 for adults ≥18 years of age) of the following symptoms havepersisted for at least 6 months: fidgeting/squirming; leaving seat;inappropriate running/climbing; difficulty with quiet activities; “onthe go;” excessive talking; blurting answers; can't wait turn, andintrusive. The combined type includes both inattentive andhyperactive-impulsive behaviors.

It is understood that the term treatment as used herein is not limitedto the cure or elimination of any condition or disorder nor is that termlimited to the achievement of certain milestones or improvement criteriain a particular subject, but includes the administration of an agent forthe purpose of achieving positive effects in terms of cognitive orbehavioral function, reduction of symptoms or side effects. All suchactivities are considered to be treatment whether or not any improvementis immediately observable or measurable.

In a highly preferred embodiment, the present invention relates to acontrolled release oral formulation of methylphenidate (or apharmaceutically acceptable salt thereof) that provides a rapid onset oftherapeutic effect and a gradual drop in plasma concentration after aprolonged period of therapeutic effect (e.g., 16 hours). This oralformulation comprises a plurality of substrates, preferably in the formof coated beads. Preferably, the coated bead comprises: (i) an initialportion of an effective dose of methylphenidate (or a pharmaceuticallyacceptable salt thereof) in immediate release form coated over granule;(ii) a controlled release (e.g., hydrophobic) material, preferably inthe form of an acrylic polymer, coated over (i); (iii) a delayed (ordistal) release (e.g., colonic delivery) coating over (ii) in an amountsufficient to substantially delay the release of the drug from thesubstrate until after coated bead passes through the stomach and thedistal part of the gastrointestinal tract; and, optionally, (iv) aremaining portion of the effective dose of methylphenidate (or apharmaceutically acceptable salt thereof) in immediate release formcoated over (iii).

Preferably, the colonic delivery coating is derived from an aqueousdispersion of an anionic copolymer based on methyl acrylate, methylmethacrylate and methacrylic acid, a plasticizer and a glidant. Thecontents of the encapsulated product may be sprinkled on soft foodsbefore administration.

The substrate (e.g., granules) can be chosen from spheres, also referredas pellets, also referred as beads, made of microcrystalline cellulose,mannitol-PVP, silica, starch, lactose, calcium carbonate or combinationthereof. The preferred substrate to be used is sugar spheres 14/18 meshto 18/20 mesh.

It can be preferred to use sugar spheres 14/18 mesh to 18/20 mesh amountof about 20% to about 70% by weight, of about 25% to about 65% byweight, of about 40% to about 64% by weight, of about 41% to about 63%by weight, of about 42% to about 62% by weight, of about 43% to about61% by weight, based on the weight of the pharmaceutical composition. Anamount of about 44.0% to about 53.5% by weight based on the weight ofthe pharmaceutical composition can be preferred of the nonpareilsubstrate, particularly of sugar spheres 14/18 mesh to 18/20 mesh.

The controlled release polymer can include ethylcellulose polymers,cellulose ethers (e.g., hydroxypropyl methylcellulose,hydroxypropylcellulose, methylcellulose, hydroxy-ethylcellulose, etc.),polyethylene oxide, polyvinyl alcohol derivates, methacrylic acidcopolymers (e.g., poly(ethylene glycol) diacrylate, poly(ethyleneglycol) triacrylate, poly(ethylene glycol) dimethacrylate, poly(ethyleneglycol) trimethacrylate, polymulti (meth)acrylates], polyethyleneglycol, polyglycolic acid, polylactic acid, poly caprolactone,poly(n-hydroxybutyrate), polyamino acids, poly(amide-enamines),poly(esters)¹, ethylene-vinyl acetate (EVA), polyvinyl pyrrolidone(PVP), poly acrylic acid (PAA), poly methacrylic acid (PMAA) orcombinations thereof in amounts that would deliver the activepharmaceutical ingredient at the desired release rate. Preferably, thecontrolled release polymer is derived from a mixture copolymer of ethylacrylate, methyl methacrylate and methacrylic acid ester with quaternaryammonium groups (Ammonio Methacrylate Copolymer, Type B USP/NF). ¹ Chem.Rev. 1999, 99, 3181-3198. Polymeric Systems for Controlled Drug Release(Uhrich et al.)

It can be preferred to use ammonio methacrylate copolymer, Type B USP/NFas a controlled release material. Such a material is commerciallyavailable from Evonik under the tradement name Eudragit® RS30D.

It thus can be preferred to use a controlled release polymer amount ofabout 3% to about 16% by weight, of about 4% to about 15% by weight, ofabout 5% to about 14% by weight, of about 5.1% to about 13.5% by weight,such as of about 8.0% by weight, of about 8.1% by weight, of about 8.2%by weight, of about 8.3% by weight, of about 8.4% by weight, of about8.5% by weight, of about 8.6% by weight, of about 8.7% by weight, ofabout 8.8% by weight, of about 8.9% by weight or about 9.0% by weight,of about 9.1% by weight, of about 9.2% by weight, of about 9.3% byweight, of about 9.4% by weight, of about 9.5% by weight, of about 9.6%by weight, of about 9.7% by weight, of about 9.8% by weight, of about9.9% by weight of about 10.0%, of about 10.1% by weight, of about 10.2%by weight, of about 10.3% by weight, of about 10.4% by weight, of about10.5% by weight, of about 10.6% by weight or of about 10.7% by weight,based on the weight of the pharmaceutical composition and the coatedbead.

An amount of about 10.0% to about 10.7% by weight based on the weight ofthe pharmaceutical composition can be preferred, particularly of ammoniomethacrylate copolymer, Type B USP/NF is used as controlled releasemodifier. The aforementioned amounts refer to the amount of allcontrolled release (e.g., hydrophobic) materials in the pharmaceuticalcomposition or coated bead.

The delayed (or distal) release (e.g., colonic delivery) coatingmaterial can include guar gum, pectin, hydroxypropyl methylcellulosephthalate, cellulose acetate phthalate, cellulose acetate trimelliate,biodegradable polysaccharides (amylose, arabinogalactan, chitosan,chondroitin sulfate, cyclodextrine, dextran, guar gum, pectin, xanthangum, xylan), poly(methacylic acid-co-methyl methacrylate) 1:2,poly(methacylic acid-co-methyl methacrylate) 1:1, polyvinyl acetatephthalate, covalent linkage of the drug with carrier (azo conjugates,cyclodextrine conjugates, glycoside conjugates, glucuronate conjugates,dextran conjugates, polypeptide conjugates, polymeric drugs), acidiccomonomers, methacryloyloxy azobenzene and 2-hydroxyethyl methacrylate(HEMA), dextran hydrogels, and combinations thereof in amounts thatwould control the delivery of the product to the distal part of the GItract. The preferred system to be used is the anionic copolymer based onmethyl acrylate, methyl methacrylate and methacrylic acid (IUPAC name:Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1).

It can be preferred to use poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 as the delayed (or distal)release (e.g., colonic delivery) material. Such a material iscommercially available from Evonik under the tradement name Eudragit®FS30D.

It thus can be preferred to use a distal release modifier amount ofabout 3% to about 20% by weight, of about 8% to about 18% by weight, ofabout 10% to about 17% by weight, of about 10.1% to about 16.5 byweight, such as of about 15.0% by weight, of about 15.1% by weight, ofabout 15.2% by weight, of about 15.3% by weight, of about 15.4% byweight, of about 15.5% by weight, of about 15.6% by weight, of about15.7% by weight, of about 15.8% by weight, of about 15.9% by weight orabout 16.0% by weight, of about 16.1% by weight, of about 16.2% byweight, of about 16.3% by weight, of about 16.4% by weight based on theweight of the pharmaceutical composition.

An amount of about 15.0% to about 16.0% by weight based on the weight ofthe pharmaceutical composition can be preferred, particularly ofpoly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1is used as distal release modifier. The aforementioned amounts refer tothe amount of all delayed (or distal) release (e.g., colonic delivery)materials (i.e., including mixtures) in the pharmaceutical compositionand the coated bead.

Plasticizers can may optionally be used. Examples of useful plasticizersinclude citrates (triethyl citrate, acetyl Triethyl citrate, tributylcitrate and acetyl tributyl citrate, acetyl tributyl citrate),triacetin, dibutyl sebacate, sebacate and azelate esters(di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, diisodecylsebacate), ester of glycol and polyhydric alcohol [propylene glycol,glycerol (glycerin), polyethylene glycol, glyceryl triacetate], glycerylmonostearate (GMS), polysorbate 80, phthalates (di-octyl phthalate,diisodecyl phthalate, diisononyl phthalate), dibutyl phthalate, diethylphthalate, adipates, phosphate esters, Polymerics, trimelliates(tris-2-ethylhexyltrimelliate), glutarates, castor oil, acetylatedmonoglycerides, fractionated coconut oil and mixtures of any two or morethereof. The preferred plasticizers to be used are triethyl citrate,glyceryl monostearate in combination with polyoxyethylene (20) sorbitanmonooleate (Polysorbate 80™).

It can be preferred to use triethyl citrate and glyceryl monostearateemulsion as plasticizer system.

It thus can be preferred to use a plasticizer system amount of about0.1% to about 10% by weight, of about 0.5% to about 9% by weight, ofabout 1% to about 7% by weight, of about 2% to about 6% by weight, ofabout 2.5% to about 5.5% by weight, of about 3.5% to about 4.5% byweight such as of about 3.6% by weight, of about 3.7% by weight, ofabout 3.8% by weight, of about 3.9% by weight, of about 4.0% by weight,of about 4.1% by weight, of about 4.2% by weight, of about 4.3% byweight, of about 4.4% by weight, of about 4.5% by weight based on theweight of the pharmaceutical composition.

An amount of about 4.0% to about 4.5% by weight based on the weight ofthe pharmaceutical composition can be preferred, particularly oftriethyl citrate and glyceryl monostearate emulsion is used asplasticizer system. The aforementioned amounts refer to the amount ofall plasticizers (i.e., including mixtures) in the composition.

Glidants can include talc, fumed silica, lecithin. The preferredglidants to be used are talc and fumed silica.

Binders can include hydroxypropyl cellulose (HPMC), hydroxypropylcellulose (HPC), polyvinyl pyrollidone, carbopol, and combinationsthereof. It can be preferred to use HMPC as a binder.

It thus can be preferred to use a binder amount of about 1% to about 10%by weight, of about 2% to about 9% by weight, of about 3% to about 7% byweight, of about 3% to about 6% by weight, such as of about 3.0% byweight, of about 3.1% by weight, of about 3.2% by weight, of about 3.3%by weight, of about 3.4% by weight, of about 3.5% by weight, of about3.6% by weight, of about 3.7% by weight, of about 3.8% by weight, ofabout 3.9% by weight, of about 4.0% by weight, of about 4.1% by weight,of about 4.2% by weight, of about 4.3% by weight, of about 4.4% byweight, of about 4.5% by weight, of about 4.6% by weight, of about 4.7%by weight, of about 4.8% by weight, of about 4.9% by weight or of about5.0% by weight, of about 5.1% by weight, of about 5.2% by weight, ofabout 5.3% by weight, of about 5.4% by weight, of about 5.5% by weight,of about 5.6% by weight, of about 5.7% by weight, of about 5.8% byweight, of about 5.9% by weight or of about 6.0% by weight, based on theweight of the pharmaceutical composition.

An amount of about 3.8% to about 6.0% by weight based on the weight ofthe pharmaceutical composition can be preferred, particularly of HPMC isused as binder. The aforementioned amounts refer to the amount of allbinders (i.e., including mixtures) in the composition.

It is preferred to use an outer layer of immediate releasemethylphenidate HCl amount of about 1% to about 30% by weight, of about5% to about 28% by weight, of about 15% to about 27% by weight, of about18% to about 25% by weight, such as of about 19.0% to about 25.0% byweight, of about 19.1% by weight, of about 19.2% by weight, of about19.3% by weight, of about 19.4% by weight, of about 19.5% by weight, ofabout 19.6% by weight, of about 19.7% by weight, of about 19.8% byweight, of about 19.9% by weight, of about 20.0% by weight, of about20.1% by weight, of about 20.2% by weight, of about 20.3% by weight, ofabout 20.4% by weight, of about 20.5% by weight, of about 20.6% byweight, of about 20.7% by weight, of about 20.8% by weight, of about20.9% by weight or of about 21.0% by weight, of about 21.1% by weight,of about 21.2% by weight, of about 21.3% by weight, of about 21.4% byweight, of about 21.5% by weight, of about 21.6% by weight, of about21.7% by weight, of about 21.8% by weight, of about 21.9% by weight orof about 22.0% by weight, based on the weight of the pharmaceuticalcomposition. An amount of about 18.0% to about 22.0% by weight based onthe weight of the pharmaceutical composition can be preferred. Theaforementioned amounts refer to the amount of methylphenidatehydrochloride or its respective amount of the base or any of its saltsin the outer immediate release layer composition.

It is also preferred to use an inner core layer of immediate releasemethylphenidate HCl amount of about 1% to about 99% by weight, of about5% to about 95% by weight, of about 60 to about 90% by weight, of about70% to about 85% by weight, such as of about 73.0% to about 83.0% byweight, of about 79.0% by weight, of about 79.1% by weight, of about79.2% by weight, of about 79.3% by weight, of about 79.4% by weight, ofabout 79.5% by weight, of about 79.6% by weight, of about 79.7% byweight, of about 79.8% by weight, of about 79.9% by weight, of about80.0% by weight, of about 80.1% by weight, of about 80.2% by weight, ofabout 80.3% by weight, of about 80.4% by weight, of about 80.5% byweight, of about 80.6% by weight, of about 80.7% by weight, of about80.8% by weight, of about 80.9% by weight or of about 81.0% by weight,of about 81.1% by weight, of about 81.2% by weight, of about 81.3% byweight, of about 81.4% by weight, of about 81.5% by weight, of about81.6% by weight, of about 81.7% by weight, of about 81.8% by weight, ofabout 81.9% by weight or of about 82.0% by weight, based on the weightof the pharmaceutical composition. An amount of about 78.0% to about82.0% by weight based on the weight of the pharmaceutical compositioncan be preferred. The aforementioned amounts refer to the amount ofmethylphenidate hydrochloride or its respective amount of the base orany of its salts in the inner core immediate release layer composition.

As described above, several solid dose controlled-release formulationsof some or all commercially available methylphenidate are commerciallyavailable in the market. However, the therapeutic effect of some or allof those formulations is not expected to last for more than 12 hoursafter administration.

An advantage of the highly preferred embodiment of the present inventionis believed to be that the formulation that will have a therapeuticeffect of at least 14 hours of duration or more. To achieve this, thedelivery of methylphenidate in the distal part of the GI tract wasinvestigated to prolong the duration of action of the drug. The presentinventors are unaware of an example of actual reported example thedelivery of methylphenidate in the distal part of the GI tract. Also, norelevant in vivo data was found reporting the release of methylphenidateor its pharmaceutically acceptable salts in the distal part of the GItract.

Methylphenidate hydrochloride is freely soluble in water and methanol,soluble in alcohol, slightly soluble in chloroform and acetone; meltsbetween 224-226° C.; and has a pKa of approximately 8.8. Methylphenidateis relatively stable in acidic solutions but it is degraded extensivelyin basic solutions. The degradation occurs via the hydrolysis of themethyl ester to the free acid, α-phenyl 1-2-piperidineacetic acid.Therefore, the degradation amount increases up to 100% as the pHincreases to 8.9. See Chemical Stability of Pharmaceuticals a Handbookfor Pharmacists 1986, 587-590 (Kenneth A. Connors, Gordon L. Amidon andValentino J. Stella) and Analytical Profiles of Drug Substances. 1981,473-497. Gandharva R. Padmanabhan for additional information.

As a result, it was not known whether methylphenidate could be absorbedsystematically in sufficient amount to have therapeutic effect at distallocations within the GI tract where the pH is known to be above pH 6.0.Thus, the present inventors performed in vitro and in vivo studies todetermine the amount released and the extent of absorption of severalmethylphenidate controlled release formulations. Table 1 shows some ofthe different formulations explored; Table 2 shows their correspondentin vitro dissolution data and FIGS. 1-4 shows their respective in vivoresults.

The preferred oral dosage form of the present invention is a capsulecontaining multilayer release (MLR) beads which have multiple layers toachieve the desire release rate profile of methylphenidatehydrochloride. Some of those layers have immediate release andcontrolled release components. It is made up of a controlled releasebead which is coated to delay dissolution until it has reached thedistal part of the GI tract. The distal coated controlled release beadhas an immediate release topcoat to provide an initial rate ofabsorption needed to have the desired therapeutic effect. In a highlypreferred embodiment, the immediate release component represents 20% ofthe total dose per bead and the controlled release component represents80% of the total dose per bead. This formulation is designed to producerapid rise to therapeutic plasma levels after oral administration, dueto the rapid dissolution and absorption of the outer immediate releaselayer, followed by a period of minimum absorption and then controlledrelease of the immediate release core, plasma levels would thengradually decrease according to the elimination kinetics ofmethylphenidate.

In a preferred embodiment, the pharmaceutical dosage forms comprisemethylphenidate or a pharmaceutical acceptable salt or derivate thereofas the sole pharmaceutically active agent.

The pharmaceutical composition of methylphenidate HCl, ControlledRelease Capsules (e.g., Formulation I and J 80:20 described below) MPHIR distal beads may comprise about 1 to 150 mg such as about 15 mg, 25mg, 30 mg, 35 mg, 45 mg, 55 mg 70 mg, 85 mg 100 mg and 120 mg

The present coated beads are preferably formulated as a singlemultilayer coated bead into an oral solid pharmaceutical compositions,preferably in the form of a capsule. The capsule material is preferablya hard gelatin capsule or a hard HPMC capsule. Other capsule materialsmay also be used and the selection thereof is within the purview of aperson of ordinary skill in the art.

In other embodiments of the present invention, it may be preferred toprovide an outer layer on the coated bead, wherein the outer layercomprises one or more salts of alginic acid. The salts of alginic acidmay be selected from sodium alginate, potassium alginate, magnesiumalginate, lithium alginate or ammonium alginate or mixtures thereof.Preferably, the salts of alginic acid may have a viscosity of 30 to 720,preferably 40 to 450, preferably 40 to 400 or preferably 50 to 300centipoise (cp) of a 1% aqueous solution (weight/weight). The provisionof such an outer layer can improve the coated bead resistance to alcohol(e.g., ethanol) in concentrations of greater than 35%(volume/volume)—e.g., 40% (volume/volume)—since such the presence ofalcohol (e.g., ethanol) in the gastric fluid usually leads to anincrease to the release rates in the stomach. Due to distributioneffect, the effect of ingested ethanol in the intestine is not of thesame importance as in the stomach. A preferred embodiment of theinvention relates to the use of coating layers described above in thecoated bead to confer resistance to alcohol (e.g., ethanol) inconcentrations of up to about 35% (volume/volume) in the gastric fluidwithout the need to use a coating comprising one or more salts ofalginic acid. Thus an effective protection against the influence ofethanol should prevent such an undesired increase of pharmaceutical ornutraceutical active ingredient in the stomach in the first place.Furthermore it may be desired that protection against the influence ofethanol shall at least not influence the comparably fast release ratesat pH 6.8 in media without ethanol.

Embodiments of the present invention will be illustrated with referencesto the following examples which should not be used to limit or otherwiseconstrue the invention.

In the examples the following abbreviations are used:

IR beads—these are beads coated with the methylphenidate hydrochloride(MPH) and having no controlled or delayed release coating;

CRIR beads—these are IR beads which have been coated with a controlledrelease coating;

ECCRIR—these are CRIR beads which have been coated with an entericcoating (similar to commercially available Biphentin® product);

DRIR beads—these are IR beads which have been coated with a delayed ordistal release coating;

DRCRIR beads—these are CRIR beads which have been coated with a delayed(enteric coating [ECCRIR]) or distal release coating; and

MPH IR distal beads—these are DRCRIR beads which have been coated withan immediate release layer of MPH.

Various of these beads were coated with sodium alginate which can conferresistance to 40% alcohol.

The general method of manufacture of Formulation I or Formulation J isdescribed below followed by the various studies and findings.

The MPH IR distal beads were manufactured in four different stagesinvolving separate coating process at each stage—immediate-releasecoating (drug layering [IR]), controlled-release coating [CR], distalrelease coating [DR] and top immediate release coating [CRDRIR]. Allfour stages are carried out in a fluid bed dryer with Wurster column.More detailed information of the process parameters used at each stageof the manufacturing process is found in Tables 9-12, respectively.

In some cases, a layer of sodium alginate-talc is also applied as afifth stage on top of the top immediate release coating to improve dosedumping of methylphenidate HCl in hydro-ethanolic solutions comparedwith coated bead formulations that do not have a layer comprising one ormore salts of alginic acid without affecting the immediate releaseperformace of the top immediate release coating. More detailedinformation of the process parameters used at this stage of themanufacturing process is found in Table 13.

The following is a description of the manufacturing process.

Example 1—IR Beads

The following protocol was used to produce the IR beads.

Add Opadry clear YS-1-7006 to water and mix, then add methylphenidatehydrochloride and stir until a clear solution is obtained.

Charge fluid bed dryer (FBD) equipped with Wurster column with sugarspheres 14-18 or 18-20 mesh.

Coat the beads at an inlet temperature of 65°±10° C. and producttemperature of 37.5°±3.5° C. by spraying the solution of methylphenidatehydrochloride.

After completion of the spraying process, allow the beads to dry at41°±4° C. for approximately 3 minutes.

Cool the beads to 30°±1° C. product temperature and weigh.

Example 2—CRIR Beads

The following protocol was used to produce the methylphenidate CR beads.

Prepare a coating dispersion by mixing Plasacryl T20, filtered (250micrometer screen) Eudragit RS 30 D and Triethyl Citrate in a containerfor at least 60 minutes.

Charge fluid bed dryer (FBD) equipped with Wurster column with IR beads.

Coat the IR beads at product temperature of 25°±5° C. by spraying thecoating dispersion.

After completion of the coating dispersion, spray rinse water at aproduct temperature of 25°±5° C.

Example 3—DRCRIR Beads, Uncured

Charge fluid bed dryer (FBD) equipped with Wurster column with CRIRbeads.

Prepare a coating dispersion by mixing Plasacryl T20, filtered (250micrometer screen) Eudragit FS 30 D and water in a container for atleast 60 minutes.

Coat the CRIR beads with Eudragit FS30D dispersion.

Note: In case the manufacturing process is interrupted, Syloid 244FP,quantity based on 0.43% of the theoretical yield of CRDR beads, is addedto the beads and blended.

Example 4—DRCRIR Beads, Cured

The following protocol was used to produce the methylphenidate DRCRbeads.

Charge fluid bed dryer (FBD) equipped with Wurster column with CRIRbeads.

Prepare a coating dispersion by mixing Plasacryl T20, filtered (250micrometer screen) Eudragit FS 30D and water in a container for at least60 minutes.

Coat the CRIR beads with Eudragit FS30D dispersion at producttemperature of 25°±3° C. by spraying the coating dispersion.

After completion of the coating dispersion, spray rinse water at aproduct temperature of 25°±3° C.

Suck into the FBD, Syloid 244FP, quantity based on 0.43% of thetheoretical yield of CRDR beads and blend.

Cure the beads at a product temperature of 40°±2° C. for 60 minutes.

Cool the beads to product temperature of 25°±3° C.

-   -   Screen the beads on 0.85 mm screen and remove fines if any.    -   Note: In case the manufacturing process is interrupted, Syloid        244FP, quantity based on 0.43% of the theoretical yield of CRDR        beads, is added to the beads and blended.

Example 5—MPH IR Distal Beads

The following protocol was used to produce the MPH IR distal beads.

Add Opadry clear YS-1-7006 to water and mix, then add methylphenidatehydrochloride and stir until a clear solution is obtained.

Charge fluid bed dryer (FBD) equipped with Wurster column with DRCRIRbeads

Coat the beads at an inlet temperature of 56°±15° C. and producttemperature of 37.5°±3.5° C. by spraying the solution of methylphenidatehydrochloride.

After completion of the solution, spray rinse water at a producttemperature of 37.5°±3.5° C.

Allow the beads to dry at product temperature of 41°±4° C. for 5minutes.

Cool the beads to 30°±1° C. product temperature and weigh.

Screen the beads and collect the beads passing through 1.8 mm screen andretained on 0.85 mm screen.

Example 6—MPH IR Distal Beads Coated with Sodium Alginate Beads

The following protocol was used to produce the MPH IR distal beadscoated with sodium alginate beads.

Add talc to water and mix; stir using a homogenizer until a uniformdispersion is obtained.

Add sodium alginate to water and mix, stir until a uniform dispersion isobtained.

Add the talc dispersion on the sodium alginate and mix until a uniformdispersion is obtained.

Charge fluid bed dryer (FBD) equipped with Wurster column with MPH IRdistal beads.

Coat the beads at an inlet temperature of 70°±15° C. and producttemperature of 50°±5° C. by spraying the solution of sodium alginate.

Allow the beads to dry at product temperature of 41°±4° C. for 5minutes.

Cool the beads to 30°±1° C. product temperature and weigh.

Screen the beads and collect the beads passing through 1.8 mm screen andretained on 0.85 mm screen.

Example 7—MPH IR Distal Beads (with or without Sodium Aginate) withSilicon Dioxide

The following protocol was used to produce these beads.

Charge V blender with approximately half the total quantity of MPH IRDistal Beads (with or without sodium aginate).

Screen Syloid FP 244 through 20 mesh screen and add to the V blender.

Load remaining quantity of MPH IR Distal Beads (with or without sodiumaginate) into the V blender.

Blend for 3 minutes.

Discharge the blend into plastic drums lined with polyethylene bags.

Example 8—Encapsulation of MPH IR Distal Beads (with or without SodiumAginate) with Silicon Dioxide

The following equipment is used during the capsule filling process ofthe MPH IR Distal Beads (with or without sodium aginate) with silicondioxide in either hard gelatin capsules (used in these Examples) or hardhypromellose (HPMC) capsules (an alternative to hard gelatin capsules):

-   -   Bosch GKF 1400 Encapsulator & Checkweigher    -   Metal Detector    -   Empty Capsule Conveying Bin

Example 9—Testing (pK Studies and Preliminary Studies on AlcoholResistance)

The following methodology was used.

The dissolution of various formulations was performed using USP paddlemethod at 100 rpm in 900 ml at 37° C. of simulated gastric fluid(without enzyme) for 2 hours, 900 ml phosphate buffer pH 6.0 for 4 hoursand 7th hour onwards, 900 mL of phosphate buffer pH 7.4. The sampleswere withdrawn at the respective time points and analysed on HPLC usingUV detector. The in vitro release data is indicated as percentagedissolved based on the label content of the active tested.

The results of a bioavailability study of this formulation indicate abiphasic release profile (FIG. 5).

It can be concluded from the in vitro dissolution data and itscorrespondent in vivo plasma concentration that methylphenidate can beabsorbed in the distal part of the GI tract. It can also be concludedthat the amount and extent of methylphenidate being absorbed depends onthe excipients used in the formulation.

FIG. 1 shows that 7 to 10% of the controlled release polymer might besufficient to provide a therapeutic effect that lasts for more than 14hours but without the desired rapid on set of action and distinctivebiphasic or triphasic pattern shown in FIG. 3 or 4. However, the nextstudy showed that increasing the amount of the controlled releasepolymer up to 20% as shown in FIG. 2 prolonged the extent of release ofmethylphenidate. Nonetheless, the higher the amount of controlledrelease polymer, the less the total amount of methylphenidate isabsorbed. This could be due to the degradation of methylphenidate athigher pH environments, thus less amount of methylphenidate is availableat distal part of the GI tract to be absorbed in systemic circulation.

Therefore, the amount of controlled release polymer needs to be adjustedaccordingly to achieve the desired distinctive in vivo plasmaconcentration pattern. In the case of the preferred embodiments of thepresent invention, the longer duration of action and distinctive patternmight be achieved between 7% to 20% weight gain of the controlledrelease polymer, more specifically about 16% weight gain of thecontrolled polymer. The 16% would provide the desired total amount andextent of methylphenidate in plasma concentration over time in adistinctive pattern that differentiates this formulation from any otherlong acting solid dose methylphenidate formulation available in themarket. Moreover, it achieves duration of action of no less than 14hours.

Formulation I also has the property that does not undergo food effect asshown in FIG. 5 and Table 3. It can also be sprinkled on apple sauce,yogurt or ice cream for up to 10 minutes without affecting itsbioavailability performance as shown in FIG. 6 and Table 5. Compared tothree equivalent doses of immediate-release methylphenidate administeredseparately at 4 hourly intervals, Formulation I has greater residuallevels of methylphenidate at hour 24 post-administration and differentpartial AUCs during the dosing interval, particularly in the 12-16 hourperiod where the pAUC is significantly larger than immediate-releasemethylphenidate (Table 4). In addition, the second peak ofmethylphenidate occurs more than 2 hours after the third peak ofimmediate-release methylphenidate (FIG. 5 and Table 4). As a result ofthe significant residual methylphenidate plasma levels at hour 24post-administration (FIG. 5), the pharmacokinetic profile changes aftermultiple days of dosing resulting in an overall increase in plasmalevels (FIG. 7 and Table 6) and higher peak concentrations. FormulationJ has a similar pharmacokinetic profile and properties as Formulation I(FIG. 8 and Table 7).

The in vitro dissolution specifications of the drug at various timepoints for formulations in accordance with Formulations A-J are shown inTable 2. Based on these results and the correlation between in vivo andin vitro data, the present inventors developed the target specificationshould in Table 8 for preferred embodiments of the present coated bead.

Based on the studies excipients were identified and adjusted to obtain afinished product that is stable within a product shelf life of at least24 months and provides no less than 14 hours of therapeutic effect.Stability testing of the above formulation showed that the total relatedsubstances at 6 months 40° C./75% RH are within 2.0% and no individualunknown is higher than 0.2%.

In vitro dissolution testing at 40% ethanol in SFG dissolution media wasperformed. As will be illustrated in Example 10, Formulation I andFormulation J were found to be resistant up to about 35% v/v and up toabout 32% v/v, respectively, ethanol in SGF. Therefore, different trialswere performed with immediate release excipients to be applied to theouter immediate release layer methylphenidate hydrochloride to increasethe ethanol resistance to 40% ethanol v/v. Some of the excipients thatwere investigated individually or in combination are: sodium alginate,Kollicoat™ IR, hypromellose, Lycoat™, pectin, lactose, methylcellulose,ethylcellulose and talc. An outer layer of these excipients was appliedon top of the desired methylphenidate CRDRIR formulation or formulationI/Formulation J and a test to determine in vitro alcohol resistance (seeExample 10 for details of the test) was performed to determine theimpact of the excipients in the formulation.

The experiment with sodium alginate in combination with talc showed thatabove 40% weight gain of sodium alginate the dissolution rate in 40% v/vethanol would impart alcohol resistance to Formulation I under theprescribed test conditions. At weight gains between 55 to 75% thedissolution rate in the first two hours of the product would meet thecriteria at 40% v/v ethanol and released about 20% of the IR component.Therefore, an improved CRDRIRR methylphenidate formulation (FormulationI or Formulation J) was developed. This formulation would have a mostouter layer of about 55-75% weight gain of sodium alginate. This layeris applied on top of the external IR layer to provide a 40% v/v ethanolresistant formulation without affecting the original release rate of theformulation.

Example 10—Testing (Further Studies on Alcohol Resistance)

Generally dose dumping is observed as a result of a compromise of therelease-rate controlling mechanism in a pharmaceutical product. Someproducts can be expected to exhibit a more rapid drug dissolution andrelease rate in the presence of ethanol. Therefore, when amodified—release product is consumed with alcohol, the modified-releasemechanism could be adversely affected, which could lead to dose dumping.

The following study was performed to evaluate the alcohol induced dosedumping in IRDR Methylphenidate HCl capsules. The effect of varyingconcentrations of ethanol on the drug release was evaluated at 0% (noethanol added), 5%, 20% and 40% ethanol which are considered to berepresentative of consumption of beer (5% ethanol), mixed drinks (20%ethanol), and neat liquor (40% ethanol). The dissolution evaluation wasalso carried out in 35% ethanol to understand the effect of ethanolconcentrations from 20% to 40% and at what level the alcohol induceddose dumping becomes significant.

The dissolution profiles showed that even though in the presence of 40%ethanol, the rate of dissolution rapidly increased as compared to thatobserved in control, the release was never considered to be dose dumpingof methylphenidate HCl. Furthermore, in the presence of 35% ethanol therate of release increased but the average percentage release amount wasdetermined to be similar when the f2, similarity factor, was calculatedagainst the control sample. The calculated value was 50. An f2 value of50-100 suggests similar dissolution profiles.

The experiments were carried out on 12 units as following: The ethanolicdissolution media used were 5%, 20%, 35% and 40% USP anhydrous ethanolin 0.1N HCl (v/v). The experiments were performed in 900 ml ofrespective media using USP apparatus 1 (baskets) at 100 rpm and 37° C.The control (0% ethanol) was also run using 900 ml of 0.1 N HCl. The 0.1N HCl was selected to approximate the conditions in the stomach.

The samples were collected every 15 minutes up to 2 hours to understandthe release profile starting as early as 15 minutes. Since thedissolution experiments were run for 2 hours, and the vessels werecovered at all times, the media evaporation had no impact on theresults. The samples were analyzed on HPLC as per specified IRDRMethylphenidate HCl capsule dissolution method and the percent releasedmethylphenidate HCl at each time point was calculated. The dissolutionand HPLC parameters are reported in Table 14.

Resistance to ethanol means that the release of the pharmaceuticalactive ingredient is in the presence of ethanol not more than 20% to bemeasured under in-vitro conditions at pH 1.2 for 2 hours in 900 mLmedium according to USP with the addition of 5, 10, 20 or 40% (v/v)ethanol at 100 rpm using USP. Dose Dumping is defined as unintended,rapid drug release in a short period of time of a significant amount ofthe drug contained in a modified release dosage form. Dose dumping shallmean that the release of the pharmaceutical active ingredient is fasterbut does not release more than 25%, no more than 20% to be measuredunder in-vitro conditions at pH 1.2 for 60 minutes in medium accordingto USP with the addition of 5, 10, 20 or 40% (v/v) ethanol.

In this study, the focus was on coating application as a function oftheoretical weight gain of coating applied to the nonpareil beads. Sinceit is also common to quantify film coating amount as mass/surface area,film coating amount (mg/cm²) was determined using a calculation forsurface area, assuming the bead is a perfect sphere:

SA=4(πr ²)

wherein SA is the surface area and r is the radius of the bead.

Conventional round nonpareil beads with diameters ranging from 0.85 to1.4 mm with an average of 1.125 mm were used in this ethanol resistancestudy. The surface area of beads of this average diameter was calculatedas follows:

SA=4(π(0.5625²))

SA=3.98 mm²

Conventional round nonpareil beads with diameters ranging from 0.85 to1.4 mm with an average of 1.125 mm were used in this ethanol resistancestudy.

Since a certain layer thickness is describe in film coating withEudragit FS30D to impart alcohol resistant properties up to 30%, up to32%, up to 35% without the capsules possessing dose dumpingcharacteristics of the active pharmaceutical ingredient within the first60 minutes; the amount of coating material is related to the surfacearea of the substrate per cm² of surface area. Thus, the inventorsdivided the surface area of a substrate A (mm²) by its weight gain w(mg), to obtain the desired coating quantity in % (w/w), i.e. as shownin the following equation:

Coating weight (%)=[A(mm²)/w(mg)]*1 (mg/cm²)

The total amount of the delayed (or distal) release (e.g., colonicdelivery) material may be in the range of from about 5% to about 35% byweight, preferably from about 10% to 30% by weight, most preferably fromabout 15 to about 25% by weight, in relation to the weight of the core.

The absolute amount of the delayed (or distal) release (e.g., colonicdelivery) material described above (prior to the examples) may, in thecase of pellets or granules with a diameter size in the range of fromabout 840 to 1410 μm, be present at an average thickness in the range infrom about 5 μm to about 50 μm, preferably from about 10 μm to about 50μm, more preferably from about 33 μm to about 47 μm, most preferablyabout 40 μm.

It can be preferred to use poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 as the delayed (or distal)release (e.g., colonic delivery) material. Such a material iscommercially available from Evonik under the tradement name Eudragit®FS30D.

The presence of ethanol in concentrations of 5, 10, 20 or 40%(volume/volume) in the gastric fluid usually leads to an increase to therelease rates in the stomach. Due to distribution effect the effect ofingested ethanol is in the intestine not of that importance as in thestomach. Thus an effective protection against the influence of ethanolshould prevent such an undesired increase of pharmaceutical activeingredient in the stomach in the first place. Furthermore it may bedesired that protection against the influence of ethanol shall at leastnot influence the comparably fast release rates at pH 6.8 in mediawithout ethanol.

International Patent Publication WO 2012/0224998 describes a gastricresistant pharmaceutical or nutraceutical composition, comprising acore, comprising a pharmaceutical or nutraceutical active ingredient anda gastric resistant coating layer onto the core, wherein the release ofthe pharmaceutical active ingredient is not more than 15% under in-vitroconditions at pH 1.2 for 2 hours in a buffered medium according to USPwith and without the addition of 40% % (v/v) ethanol, wherein thegastric resistant coating layer comprises 10 to 10% by weight of one ormore salts of alginic acid with a viscosity of 30 to 720 cP of a 1%aqueous solution. The one layer system as described is stated to solvethe problem of protection against the influence of ethanol. However,there is no reference of ethanol protection provided by coating layercontaining Eudragit FS30D at any ethanol concentration by itself or whenthe coatings which include the ammonium alginate, coatings which employother alginate salts, like sodium or potassium alginate, are depositedin the most outer layer of the bead.

The data demonstrated that the in-vitro rate of dissolution ofmethylphenidate HCl did not increase in the presence of 5% and 20%ethanol within two hours as compared to that in control; and thein-vitro rate of dissolution of methylphenidate HCl did not increase inthe presence of 5%, 20%, 35% and 40% ethanol within 30 minutes ascompared to that in control. Nevertheless, in the presence of 35% and40% ethanol, more rapid increase was observed in the dissolution releaserate after 30 minutes. Even though a faster release was observed, therelease of the active pharmaceutical ingredients was still in acontrolled release manner. Dose dumping of methylphenidate hydrochloridedid not occur at any time of the release in presence of differentconcentration of ethanol up to 40%.

The results of this study are believed to be a reasonable basis for thepresent inventors to predict similar resistance to alcohol (e.g.,ethanol) would be observed clinically and for active ingredients otherthan methylphenidate HCl.

Example 11—a Randomized, Double-Blind Study of the Time Course ofResponse of MPH-IR Distal Bead (Formulation I) in Adult with ADHD in aSimulated Adult Workplace Environment (AWE)

Objectives

The purpose of this randomized, double-blind, crossover,placebo-controlled, optimized-dose study was to assess the clinicalefficacy, time of onset and time course of efficacy over 16 hours ofMPH-IR Distal Bead compared to placebo in adults diagnosed with ADHD inan AWE setting.

Methodology

This study (063-008) was a randomized, double-blind, placebo-controlledcross-over study in adult, male and female ADHD subjects conducted toassess clinical efficacy, the time of onset and time course of efficacyof MPH-IR Distal Bead measured by the Permanent Product Measure ofPerformance (PERMP) (an objective, skill-adjusted math test thatmeasures attention in ADHD) score. Subjects were titrated to an optimaldose in an open-label phase of between 2 and 7 weeks, familiarized withstudy procedures in a practice AWE session and then randomized to one oftwo sequences (ACTIVE to PLACEBO or PLACEBO to ACTIVE) and received onetreatment for one week, followed by an AWE session, then crossed over tothe other treatment for one week, followed by a second AWE session.

Number of Subjects

Planned: 60 subjects. Randomised: 59 subjects. Completed: 46 subjects.

Test Treatment, Dose, and Mode of Administration

Active or matching placebo MPH-IR Distal Bead (methylphenidatehydrochloride controlled-release—Formulation I in Table 1) 25, 35, 45,55, 70, 85 or 100 mg oral capsules were administered once-daily in themorning.

Duration of Treatment

Subjects received open label medication during a 2 to 9 week dosetitration, followed by a double-blind crossover of one week of placebotreatment and one week of active treatment.

Criteria for Evaluation

The primary outcome measure was the mean between-treatment PERMP Totalscore across the AWE sessions. Secondary outcome measures included theonset and time course of efficacy of MPH-IR Distal Bead compared toplacebo as measured by the PERMP Total Score (PERMP-T), PERMP AttemptedScore (PERMP-A) and PERMP Correct Score (PERMP-C) at pre-dose and 1.0,2.0, 5.0, 8.0, 11.0, 14.0 and 16.0 hours post-dose and the onset andtime course of efficacy of MPH-IR Distal Bead compared to placebo asmeasured by the SKAMP (a subjective measure of behaviour), using thecombined score (SKAMP-C), the SKAMP-Deportment (SKAMP-D) subscale andSKAMP Attention (SKAMP-A) subscale at pre-dose and 0.5, 1.0, 2.0, 4.0,5.0, 7.0, 8.0, 11.0, 13.0, 14.0 and 16.0 hours post-dose.

Efficacy & Safety Results

The study met the primary endpoint in that subjects treated with MPH-IRDistal Bead had improved attention compared to subjects receivingplacebo, as measured by the mean change from pre-dose PERMP-Total Scores(FIG. 9).

Subjects receiving MPH-IR Distal Bead showed improvement in attentionwith an onset of action within 1.0 hour of receiving active medicationcompared to placebo with duration of effect continuing for up to andincluding 16.0 hours post-dose, based on change from pre-dose LS meandifference from placebo PERMP-Total Scores (FIG. 9).

Subjects receiving MPH-IR Distal Bead showed improvement in behaviourwith an onset of action within 1.0 hour of receiving active medicationcompared to placebo with duration of effect continuing for up to andincluding 16.0 hours post-dose based on change from pre-dose LS meandifference from placebo SKAIVIP-C Scores (FIG. 10).

MPH-IR Distal Bead was relatively safe and well-tolerated medication.

Overall Conclusions

MPH-IR Distal Bead was safe and effective in the treatment of adultswith ADHD, demonstrating efficacy from one hour to 16 hours postadministration on both objective and subjective measures. Subjectsdemonstrated significant improvement in the primary endpoint—anobjective measure of attention (the PERMP)—and the secondary endpoint—asubjective measure of behaviour (the SKAMP)—during the double-blindphase of the study when treated with MPH-IR Distal Bead compared to whentreated with placebo.

In addition, the study medication was well-tolerated, with no seriousadverse events. Patients reported satisfaction with ability to fallasleep, appetite for lunch, appetite for dinner or overall adverseeffects and no significant differences compared to placebo in sleepquality.

The onset and duration of action at one hour and 16 hourspost-administration respectively, is the result of the pharmacokineticprofile of MPH-IR Distal Bead. The residual methylphenidate plasmaconcentration at hour 24 post-administration leads to an increase in thefirst peak of methylphenidate following multiple days of dosing,resulting in an onset of action with one hour. In addition, the secondpeak of methylphenidate is also increased following multiple days ofdosing, providing sufficient plasma levels of methylphenidate late inthe day that results in a prolonged duration of action extending to 16hours post-administration. The pharmacokinetic profile of thisformulation provides a combination of rapid onset and a prolongedduration of action in a single daily administration.

Example 12—Preferred Formulations

Based on the exemplary work described above, Formulations I and J wereidentified as the most preferred for the present coated bead. Tables 15and 16 provide complete formulation specifications for oral solidpharmaceutical composition based on Formulations I and J, respectivelyfor the following dosage strengths of methylphenidate HCl: 25 mg, 30,mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg and 100 mg.

While this invention has been described with reference to illustrativeembodiments and examples, the description is not intended to beconstrued in a limiting sense. Thus, various modifications of theillustrative embodiments, as well as other embodiments of the invention,will be apparent to persons skilled in the art upon reference to thisdescription. It is therefore contemplated that the appended claims willcover any such modifications or embodiments.

All publications, patents and patent applications referred to herein areincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

TABLE 1 Strength (label claim) 20 mg Strength (label claim) 20 mgFormulation A - 7% Formulation B - 10% Formulation C - 16% FormulationD - 20% 063-001 063-001 063-002 063-002 DRCRIR bead DRCRIR bead DRCRIRbead DRCRIR bead Quantity Quantity Quantity Quantity Ingredient per unit% per unit % per unit % per unit % Methylphenidate HCl, USP 20.0 11.2520.0 10.88 20.0 10.19 20.0 9.79 Sugar spheres 14/18 mesh, 107.0 60.2107.0 58.2 107.0 54.5 106.8 52.3 USP/NF Opadry Clear YS-1-7006, USP 6.43.6 6.4 3.5 6.5 3.3 6.4 3.1 Ammonio methacrylate 9.4 5.26 13.3 7.24 21.310.86 26.7 13.05 copolymer dispersion, Type B, 30% dispersion (EudragitRS30D Solids), NF Triethyl Citrate, USP/NF 1.4 0.80 2.0 1.10 3.3 1.674.1 2.00 Glyceryl monostearate 3.8 2.18 4.3 2.37 5.3 2.74 6.0 2.94emulsion (Plasacryl T20), HS Silicon dioxide, (Syloid 0.7 0.4 0.7 0.40.8 0.4 0.8 0.4 244FP), NF Eudragit FS30D Liquid, HS 29.0 16.32 30.016.32 32.0 16.32 33.3 16.32 Total weigh in capsule (mg) ~178 ~100 ~184~100 ~196 ~100 ~204 ~100 Strength (label claim) 30 mg Strength (labelclaim) 30 mg Formulation E - 70:30 Formulation F - 80:20 063-002 063-003ECCRIR bead (70%) + DRCRIR bead (80%) + DRCRIR bead (30%) IR bead (20%)Ingredient Quantity per unit (%) Quantity per unit (%) 1. IR bead IRbead (0%) IR bead (20%) Methylphenidate HCl, USP — 15.0 Sugar spheres14/18 mesh, USP/NF — 80.2 Opadry Clear YS-1-7006, USP — 4.8 Total IRbead — ~100% 7. CR/EC/IR bead ECCRIR bead (70%) ECCRIR bead (0%)Methylphenidate HCl, USP 12.78 — Sugar spheres 14/18 mesh, USP/NF 62.02— Opadry Clear YS-1-7006, USP 4.04 — Ammonio methacrylate copolymerdispersion, Type B, 5.44 — 30% dispersion (Eudragit RS30D Solids), NFMethacrylic Acid copolymer dispersion, 30% 8.15 — dispersion (EudragitL30 D-55 solids), USP NF Triethyl Citrate, USP/NF 2.70 — Talc Ph.Eur/USP 4.87 — Total CR/EC/IR bead ~100% ~100% 6. CR/DR bead DRCRIR bead(30%) DRCRIR bead (80%) Methylphenidate HCl, USP 10.19 10.19 Sugarspheres 14/18 mesh, USP/NF 54.5 54.5 Opadry Clear YS-1-7006, USP 3.3 3.3Ammonio methacrylate copolymer dispersion, Type B, 10.86 10.86 30%dispersion (Eudragit RS30D Solids), NF Triethyl Citrate, USP/NF 1.671.67 Glyceryl monostearate emulsion (Plasacryl T20), HS 2.74 2.74Silicon dioxide, (Syloid 244FP), NF 0.4 0.4 Eudragit FS30D Liquid, HS16.32 16.32 Total CR/DR bead (30%) ~100% ~100% Total weight in capsule~211 mg ~275 mg Strength (label claim) 30 mg Strength (label claim) 30mg Formulation G - 30:55:15 Formulation H - 35:55:10 063-003 063-003ECCRIR bead (30%) + ECCRIR bead (35%) + DRCRIR bead (55%) + DRCRIR bead(55%) + IR bead (15%) IR bead (10%) Ingredient Quantity per unit (%)Quantity per unit (%) 1. IR bead IR bead (15%) IR bead (10%)Methylphenidate HCl, USP 15.0 15.0 Sugar spheres 14/18 mesh, USP/NF 80.280.2 Opadry Clear YS-1-7006, USP 4.8 4.8 Total IR bead ~100% ~100% 7.CR/EC/IR bead ECCRIR bead (30%) ECCRIR bead (35%) Methylphenidate HCl,USP 12.78 12.78 Sugar spheres 14/18 mesh, USP/NF 62.02 62.02 OpadryClear YS-1-7006, USP 4.04 4.04 Ammonio methacrylate copolymerdispersion, Type B, 5.44 5.44 30% dispersion (Eudragit RS30D Solids), NFMethacrylic Acid copolymer dispersion, 30% dispersion 8.15 8.15(Eudragit L30 D-55 solids), USP NF Triethyl Citrate, USP/NF 2.70 2.70Talc Ph. Eur/USP 4.87 4.87 Total CR/EC/IR bead ~100% ~100% 6. CR/DR beadDRCRIR bead (55%) DRCRIR bead (55%) Methylphenidate HCl, USP 10.19 10.19Sugar spheres 14/18 mesh, USP/NF 54.5 54.5 Opadry Clear YS-1-7006, USP3.3 3.3 Ammonio methacrylate copolymer dispersion, Type B, 10.86 10.8630% dispersion (Eudragit RS30D Solids), NF Triethyl Citrate, USP/NF 1.671.67 Glyceryl monostearate emulsion (Plasacryl T20), HS 2.74 2.74Silicon dioxide, (Syloid 244FP), NF 0.4 0.4 Eudragit FS30D Liquid, HS16.32 16.32 Total CR/DR bead (30%) ~100% ~100% Total weight in capsule~262 mg ~264 mg Strength (label claim) 100 mg Strength (label claim) 100mg Formulation F 80:20 Formulation I 80:20 Strength (label claim) 100 mg063-003 063-004, 063-005, Formulation J 80:20 DRCRIR bead + 063-007063-008 063-011 IR bead MPH IR distal bead MPH IR distal bead IngredientQuantity per unit (%) Quantity per unit (%) Quantity per unit (%) 1. IRbead IR bead (20%) IR bead (0%) IR bead (0%) Methylphenidate HCl, USP15.0 — — Sugar spheres 14/18 mesh, USP/NF 80.2 — — Opadry ClearYS-1-7006, USP 4.8 — — Total IR bead ~100% — — 6. CR/DR bead DRCRIR bead(80%) DRCRIR bead (0%) DRCRIR bead (0%) Methylphenidate HCl, USP 10.19 —— Sugar spheres 14/18 mesh, USP/NF 54.5 — — Opadry Clear YS-1-7006, USP3.3 — — Ammonio methacrylate copolymer 10.86 — — dispersion, Type B, 30%dispersion (Eudragit RS30D Solids), NF Triethyl Citrate, USP/NF 1.67 — —Glyceryl monostearate emulsion 2.74 — — (Plasacryl T20), HS Silicondioxide, (Syloid 244FP), NF 0.4 — — Eudragit FS30D Liquid, HS 16.32 — —Total CR/DR bead ~100% — — 8. CR/DR/IR bead MPH IR distal bead MPH IRdistal bead Quantity per Quantity per MPH IR distal bead unit (mg) %unit (mg) % Methylphenidate HCl, USP — 100 12.3 100 18.4 Sugar spheres14/18 mesh or 18/20 — 428.5 52.7 243.1 44.7 mesh, USP/NF Opadry ClearYS-1-7006, USP — 31.7 3.9 32.2 5.9 Ammonio methacrylate copolymer — 85.410.5 55.55 10.3 dispersion, Type B, 30% dispersion (Eudragit RS30DSolids), NF Triethyl Citrate, USP/NF — 13.0 1.6 8.61 1.6 Glycerylmonostearate emulsion — 22.0 2.7 14.1 2.6 (Plasacryl T20), HS Silicondioxide, (Syloid 244FP), NF — 4.1 0.5 4.52 0.8 Eudragit FS30D Liquid, HS— 128.5 15.8 84.61 15.6 Total weight in capsule ~1100 mg ~813 mg ~100%~543 mg ~100%

TABLE 2 Dissolution results % Methylphenidate HCl dissolved Time Formu-Formu- Formu- Formu- Formu- Formu- Formu- Formu- Formu- Formu-Dissolution (hours) lation A lation B lation C lation D lation E lationF lation G lation H lation I lation J USP paddle method, 1 4 4 1 1 25 1825 24 20 20 100 rpm, at 37° C., 900 ml 4 11 10 3 4 31 22 29 28 21 21simulated gastric fluid for 2 8 41 49 28 38 54 46 61 61 44 41 hours, 900ml phosphate buffer 12  68 76 44 40 64 58 71 71 83 73 pH 6.0 for 4 hoursand 7th 16¹ 79 78 54 41 68 67 74 73 78 79 hour onwards, 900 mL ofphosphate buffer pH 7.4 USP<711>Acceptance Table 2 ¹The total amount ofMethylphenidate HCl decreases as it degrades at pH 7.4

TABLE 3 Ratios, 90% Geometric CI for non-dose-normalized ParametersStudy 063-004 90% Geometric C.I. Parameter Treatment Comparisons RatioLower Upper AUC_(0-t) Formulation I (fed) vs IR-MPH (fed) 102.73% 97.69%108.03% Formulation I (fast) vs IR-MPH (fast) 123.92% 117.87% 130.29%Formulation I (fed) vs (fast) 98.02% 93.21% 103.07% AUC_(0-inf)Formulation I (fed) vs IR-MPH (fed) 128.07% 122.18% 134.24% FormulationI (fast) vs IR-MPH (fast) 147.91% 141.31% 154.83% Formulation I (fed) vs(fast) 102.09% 97.41% 107.01% C_(max) Formulation I (fed) vs IR-MPH(fed) 71.17% 65.92% 76.83% Formulation I (fast) vs IR-MPH (fast) 87.06%80.66% 93.96% Formulation I (fed) vs (fast) 89.31% 82.73% 96.41%

TABLE 5 Ratios, 90% Geometric CI for non-dose- normalized ParametersStudy 063-005 90% Geometric C.I. Parameter Treatment Comparisons RatioLower Upper AUC0-t Test(A) - Reference(D) 98.78% 95.30% 102.40%Test(B) - Reference(D) 98.60% 95.11% 102.22% Test(C) - Reference(D)101.08% 97.52% 104.78% AUC0-inf Test(A) - Reference(D) 97.87% 94.45%101.41% Test(B) - Reference(D) 98.45% 95.01% 102.02% Test(C) -Reference(D) 101.35% 97.82% 105.01% Cmax Test(A) - Reference(D) 108.31%100.05% 117.26% Test(B) - Reference(D) 100.08% 92.43% 108.37% Test(C) -Reference(D) 105.84% 97.77% 114.57%

TABLE 4 Summary of non-dose-normalized Pharmacokinetic Results Study063-004 Formulation I Formulation I Ritalin Ritalin (100 mg Fast) (100mg Fed) (20 mg x 3 Fast) (20 mg x 3 Fed) AUC_(0-t) 167783.86 ± 46487.66 161271.48 ± 40500.38 132957.12 ± 43955.82 155290.78 ± 37540.22 (pg ·hr/mL) AUC_(0-inf) 205610.43 ± 61472.88  202964.28 ± 57449.88 136436.27± 45902.96 159381.72 ± 39469.43 (pg · hr/mL) Residual Area 17.62 ± 11.0618.63 ± 8.51  2.42 ± 0.96  2.45 ± 0.92 (%) C_(max) 12875.81 ± 4590.85 11088.11 ± 2699.06 14105.39 ± 3770.36 15247.79 ± 3288.76 (pg/mL) T_(max)(hr) 11.5 12.5 9.50 6.04 K_(el) (1/hr) 0.1173 ± 0.0430  0.1074 ± 0.0296 0.1968 ± 0.0218  0.1976 ± 0.0247 T_(1/2 el) 6.95 ± 3.25  7.03 ± 2.28 3.57 ± 0.40  3.56 ± 0.45 (hr) AUC₀₋₄ 24818.34 ± 7976.76  21160.21 ±6420.56 22955.21 ± 8292.78 26886.10 ± 7606.67 (pg · hr/mL) AUC₈₋₁₂36457.19 ± 18489.84 29392.15 ± 8453.72  41094.69 ± 12181.51 44914.86 ±8753.20 (pg · hr/mL) AUC₁₂₋₁₆ 39322.95 ± 10236.29  36653.88 ± 11521.1420364.91 ± 9558.52 24467.89 ± 8948.65 (pg · hr/mL) AUC₀₋₈ 48626.93 ±16709.44 47422.42 ± 9947.71  58725.69 ± 17067.12  70056.85 ± 16031.58(pg · hr/mL) AUC₀₋₁₂ 85084.12 ± 33395.48  76814.57 ± 16722.84  99820.38± 28132.26 114971.70 ± 23607.37 (pg · hr/mL) AUC₀₋₁₆ 124407.07 ±40902.66  113468.45 ± 26835.93 120185.29 ± 37077.85 139439.59 ± 30402.02(pg · hr/mL) AUC₀₋₂₄ 167740.82 ± 46495.35  161217.02 ± 40475.17132949.12 ± 43953.43 155281.82 ± 37538.47 (pg · hr/mL) AUC₄₋₈ 23500.00 ±10293.79 25814.81 ± 6376.73 35446.96 ± 9454.91  42739.42 ± 10194.06 (pg· hr/mL) AUC_(12-t) 82699.74 ± 21862.39  84456.90 ± 26718.88  33136.74 ±16892.19  40319.08 ± 17657.25 (pg · hr/mL) C_(max0-4) (pg/mL) 9365.42 ±3213.96  9248.95 ± 1886.65  9206.46 ± 3371.78 10951.60 ± 3222.66C_(max4-8) (pg/mL) 7927.79 ± 4347.57  8162.71 ± 1932.67 12684.06 ±3583.22 14454.13 ± 3450.37 C_(max8-16) (pg/mL) 12413.97 ± 4546.66 10667.64 ± 3017.29 13650.77 ± 3689.34 14174.43 ± 3158.31 T_(max0-4) (hr) 1.63  3.00 2.00 2.07 T_(max4-8) (hr)  4.00  3.95 6.00 6.00 T_(max8-16)(hr) 12.5 13.5 9.52 10.0 

TABLE 6 Ratios, 90% Geometric CI for non-dose- normalized ParametersStudy 063-007 90% Geometric C.I. Parameter Treatment Comparisons RatioLower Upper AUC₀₋₂₄ Formulation I vs 147.61% 143.02% 152.34% IR-MPHC_(max) Formulation I vs 98.92% 92.48% 105.81% IR-MPH C_(min)Formulation I vs 456.91% 404.67% 515.90% IR-MPH

TABLE 7 Ratios, 90% Geometric CI Parameters for Study 063-011 90%Geometric C.I. Parameter Treatment Comparisons Ratio Lower UpperAUC_(0-t) Formulation I vs 99.15% 91.82% 107.08% Formulation J (fed)Formulation I vs 99.64% 92.27% 107.61% Formulation J (fast) AUC_(0-inf)Formulation I vs 98.66% 91.67% 106.20% Formulation J (fed) Formulation Ivs 98.76% 91.75% 106.29% Formulation J (fast) C_(max) Formulation I vs98.34% 83.67% 115.60% Formulation J (fed) Formulation I vs 90.87% 77.31%106.81% Formulation J (fast)

TABLE 8 Time (hours) % Methylphenidate HCl dissolved 1 NLT 15% 4 18-38%8 35-55% 12 68-98  16 NLT 68

TABLE 9 Production of Methylphenidate Immediate Release (IR) BeadsProcess Parameters Coating sugar spheres with Recommended Parametersmethylphenidate solution Preheating Fluid bed coating Inlet air volume,cmh (to 800 ± 300 1100 ± 200  be adjusted as necessary) Inlet airtemperature, ° C. 56 ± 5  65 ± 10 Atomization air pressure, bar  1 ± 0.23 ± 1 Inlet dew point, ° C. 8 ± 4 8 ± 4 Product temperature, ° C. 35 ±2  37.5 ± 3.5  Spraying rate, g/min (to N/A 150-400 be adjusted asnecessary) Rinsing with purified water Rinsing Drying Cooling Amount ofwater used (kg) 1 N/A N/A Fluidized air volume, cmh 1100 ± 200  1000 ±200 1000 ± 300 (to be adjusted as necessary) Inlet air temperature, ° C.65 ± 10 60 ± 6 Minimum (to be adjusted as necessary) Atomization airpressure, bar 3 ± 1   1 ± 0.2   1 ± 0.2 Inlet dew point, ° C. 8 ± 4  8 ±4  8 ± 4 Product temperature, ° C. 36 ± 3  41 ± 4 30 ± 1 Spraying rate,g/min (to 150-350 N/A N/A be adjusted as necessary) Time, min N/A ~3 N/A

TABLE 10 Production of Methylphenidate Controlled Release (CRIR) BeadsProcess Parameters Coating IR beads with Controlled Release RecommendedParameters coating dispersion Preheating CR Coating Rinsing Amount ofpurified N/A N/A 1 water used (Kg) Inlet air volume, cmh 1000 ± 250 1250± 350  1250 ± 250  (to be adjusted as necessary) Inlet air temperature,° C. 45 ± 5 45 ± 15 45 ± 15 Atomization air pressure, bar   1 ± 0.2 2.8± 0.5 2.8 ± 0.5 Inlet dew point, ° C.  8 ± 4 8 ± 4 8 ± 4 Producttemperature, ° C. 25 ± 3 25 ± 5  25 ± 5  Spraying rate, g/min N/A100-400 100-350 (to be adjusted as necessary)

TABLE 11 Production of Methylphenidate Distal (DRCRIR) Beads, curedProcess Parameters Coating CRIR beads with Distal Recommended ParametersRelease coating dispersion DR Coating Rinsing Curing Cooling Amount ofpurified water used (Kg) N/A 1 N/A N/A Inlet air volume, cmh 1400 ± 400 1400 ± 400  800 ± 400 800 ± 100 (to be adjusted as necessary) Inlet airtemperature, ° C. 45 ± 15 45 ± 15 To be 15 ± 10 adjusted Atomization airpressure, bar 2.8 ± 0.5 2.8 ± 0.5  1 ± 0.2  1 ± 0.2 Inlet dew point, °C. 8 ± 4 8 ± 4 8 ± 4 8 ± 4 Product temperature, ° C. 25 ± 3  25 ± 3  40± 2  25 ± 3  Spraying rate, g/min 150-400 150-350 N/A N/A (to beadjusted as necessary) Time, min. N/A N/A 60 N/A

TABLE 12 Production of Methylphenidate IR Distal (MPH IR distal) BeadsProcess Parameters Coating DRCRIR beads with Recommended ParametersImmediate Release layer Preheating IR coating Rinsing Drying CoolingAmount of purified water used (Kg) N/A N/A 1 N/A N/A Inlet air volume,cmh 1100 ± 400 1400 ± 400 1400 ± 400 1100 ± 400 1100 ± 400 (to beadjusted as necessary) Inlet air temperature, ° C.  56 ± 15  56 ± 15  56± 15 To be  20 ± 10 adjusted Atomization air pressure, bar   3 ± 0.5   3± 0.5   3 ± 0.5   1 ± 0.2   1 ± 0.2 Inlet dew point, ° C.  8 ± 4  8 ± 4 8 ± 4  8 ± 4  8 ± 4 Product temperature, ° C. 36 ± 3 37.5 ± 3.5 37.5 ±3.5 41 ± 4 30 ± 1 Spraying rate, g/min N/A 150-400 150-350 N/A N/A (tobe adjusted as necessary) Time, min. 5-10 N/A N/A 5 N/A

TABLE 13 Production of Methylphenidate IR (MPH IR distal) Beads coatedwith Sodium Alginate Recommended Parameters Process Parameters SodiumCoating MPH IR distal beads Alginate with sodium alginate layerPreheating coating Drying Cooling Amount of purified water used (Kg) N/AN/A N/A N/A Inlet air volume, cmh 1100 ± 400 1400 ± 400 1100 ± 400 1100± 400 (to be adjusted as necessary) Inlet air temperature, ° C.  70 ± 15 70 ± 15 To be  20 ± 10 adjusted Atomization air pressure, bar   3 ± 0.5  3 ± 0.5   1 ± 0.2   1 ± 0.2 Inlet dew point, ° C.  8 ± 4  8 ± 4  8 ± 4 8 ± 4 Product temperature, ° C. 52 ± 5 52 ± 5 41 ± 4 30 ± 1 Sprayingrate, g/min N/A 50-300 N/A N/A (to be adjusted as necessary) Time, min.5-10 N/A 5 N/A

TABLE 14 Dissolution Parameters (Example 10) Equipment ConditionsApparatus Basket, USP apparatus 1 Speed 100 rpm Bath temperature: 37° C.Dissolution media 900 ml 0%, 5%, 20%, 35% or 40% ethanol v/v in 0.1N HClSampling time points 15, 30, 45, 60, 75, 90, 105, 120 minutes

TABLE 15 Composition of the dosage form (Formulation I 80:20) MPH IRdistal: Quantity per capsule (mg) per Strength (label claim) approx:Ingredient 25 mg 30 mg 35 mg 45 mg 55 mg 70 mg 85 mg 100 mg %Methylphenidate HCl, USP 25 30 35 45 55 70 85 100 12.3 Sugar spheres14/18 mesh, 107.1 128.5 150.0 192.8 235.7 299.9 364.2 428.5 52.7 USP/NFOpadry Clear YS-1-7006 7.9 9.5 11.1 14.3 17.4 22.2 27.0 31.7 3.9 Ammoniomethacrylate 21.3 25.6 29.9 38.4 47.0 59.8 72.6 85.4 10.5 copolymerdispersion, Type B, 30% dispersion (Eudragit RS30D Solids), NF TriethylCitrate, USP/NF 3.3 3.9 4.6 5.9 7.2 9.1 11.1 13.0 1.6 Glycerylmonostearate 5.5 6.6 7.7 9.9 12.1 15.4 18.7 22.0 2.7 emulsion (PlasacrylT20), HS, solids Silicon dioxide, (Syloid 1.0 1.2 1.4 1.8 2.2 2.8 3.54.1 0.5 244FP), NF Eudragit FS30D, HS, 32.1 38.5 45.0 57.8 70.7 89.9109.2 128.5 15.8 solids TOTAL (approx.) 203 244 285 366 447 569 691 813100

TABLE 16 Composition of the dosage form (Formulation J 88:20) MPH IRdistal: Quantity per capsule (mg) per Strength (label claim) approx:Ingredient 25 mg 30 mg 35 mg 45 mg 55 mg 70 mg 85 mg 100 mg %Methylphenidate HCl, USP 25 30 35 45 55 70 85 100 18.4 Sugar spheres14/18 mesh, 60.8 72.9 84.9 109.5 133.7 169.9 206.5 243.1 44.7 USP/NFOpadry Clear YS-1-7006 8.0 9.6 11.2 14.5 17.6 22.4 27.3 32.2 5.9 Ammoniomethacrylate 14.0 16.8 19.6 25.2 30.8 39.1 47.6 55.55 10.3 copolymerdispersion, Type B, 30% dispersion (Eudragit RS30D Solids), NF TriethylCitrate, USP/NF 2.2 2.6 3.0 3.9 4.8 6.1 7.4 8.61 1.6 Glycerylmonostearate 3.5 4.3 4.9 6.4 7.8 9.9 12.0 14.1 2.6 emulsion (PlasacrylT20), HS, solids Silicon dioxide, (Syloid 1.1 1.3 1.5 2.0 2.4 3.0 3.74.52 0.8 244FP), NF Eudragit FS30D, HS, 21.2 25.4 29.6 38.2 46.6 59.372.1 84.61 15.6 solids TOTAL (approx.) 136 163 190 245 299 380 462 543100

What is claimed is:
 1. A dosage form comprising an immediate releasemethylphenidate hydrochloride component and a controlled/delayed releasemethylphenidate hydrochloride component, wherein the immediate releasemethylphenidate component and the controlled/delayed releasemethylphenidate component, together, provide 25, 35, 45, 55, 70, 85, or100 mg of methylphenidate hydrochloride; wherein upon oraladministration, the dosage form provides efficacious treatment ofattention deficit hyperactivity disorder (“ADHD”) for 16 hours after asingle oral administration; and wherein the dosage form has an in vitromethylphenidate hydrochloride dissolution rate, and wherein the in vitromethylphenidate hydrochloride dissolution rate does not increase in thepresence of 5% or 20% ethanol when measured under in vitro conditionswith stirring at 100 rpm at pH 1.2 for 2 hours in 900 mL of a mediumcomprising up to about either 5% or 20% v/v ethanol.
 2. The dosage formof claim 1, wherein not more than 20% of the methylphenidatehydrochloride in the dosage form is released over 2 hours when measuredunder in vitro conditions with stirring at 100 rpm at pH 1.2 for 2 hoursin 900 mL of a medium comprising up to about 20% v/v ethanol.
 3. Themethod of claim 16, wherein not more than 20% of the methylphenidatehydrochloride in the dosage form is released over 2 hours when measuredunder in vitro conditions with stirring at 100 rpm at pH 1.2 for 2 hoursin 900 mL of a medium comprising up to about 5% v/v ethanol.
 4. Thedosage form of claim 1, wherein the dosage form has the following invitro methylphenidate dissolution profile: Time (hours) Methylphenidate(% dissolved) 1 NLT 15% 4 18-38% 8 35-55% 12 68-98  16 NLT 68

when tested according to the USP paddle dosage form, 100 rpm, at 37° C.;(i) starting with 900 ml simulated gastric fluid for 2 hours, (ii)followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) forthe 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP<711>Acceptance Table
 2. 5. The dosage form of claim 1, wherein thecontrolled/delayed release methylphenidate hydrochloride component andthe immediate release methylphenidate component are provided via aplurality of coated beads.
 6. The dosage form of claim 5, wherein eachbead comprises a portion of the controlled/delayed releasemethylphenidate hydrochloride component and a portion of the immediaterelease methylphenidate component.
 7. The dosage form of claim 6,wherein each bead in the plurality of beads comprises a core comprisinga first amount of methylphenidate hydrochloride corresponding to theportion of the delayed/controlled release methylphenidate hydrochloridecomponent.
 8. The dosage form of claim 7, wherein the core comprises agranule coated with the first amount of methylphenidate hydrochloride orwherein the core comprises a granule substrate in admixture with thefirst amount of methylphenidate hydrochloride.
 9. The dosage form ofclaim 9, wherein the first amount of methylphenidate hydrochloride iscoated with an inner controlled release coating and an outer delayedrelease coating coated over the inner controlled release coating. 10.The dosage form of claim 10, wherein a second amount of methylphenidatehydrochloride, corresponding to the portion of the immediate releasemethylphenidate component, is coated over the outer delayed releasecoating.
 11. The dosage form of claim 11, wherein the delayed/controlledrelease methylphenidate hydrochloride component comprises about 78weight percent to about 82 weight percent of the 25, 35, 45, 55, 70, 85,or 100 mg of methylphenidate hydrochloride in the pharmaceuticalcomposition.
 12. The dosage form of claim 12, wherein thedelayed/controlled release methylphenidate hydrochloride componentcomprises about 80 weight percent of the 25, 35, 45, 55, 70, 85, or 100mg of methylphenidate hydrochloride in the pharmaceutical compositionand wherein the immediate release methylphenidate component providesabout 20 percent by weight of the 25, 35, 45, 55, 70, 85, or 100 mgmethylphenidate hydrochloride in the pharmaceutical composition.
 13. Thedosage form of claim 10, wherein the inner controlled release coating ispresent in an amount of about 3 percent to about 16 percent by weight ofeach bead in the plurality of coated beads, and wherein the outerdelayed release coating is present in an amount of from about 3 percentto about 20 percent by weight of each bead in the plurality of coatedbeads.
 14. The dosage form of claim 13, wherein the inner controlledrelease coating comprises ammonio methacrylate copolymer, Type B USP/NF.15. The dosage form of claim 14, wherein the outer delayed releasecoating comprises poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1.
 16. A method of treatingattention deficit hyperactivity disorder (ADHD) in a subject in needthereof, the method comprising orally administering to the subject adosage form providing 25, 35, 45, 55, 70, 85, or 100 mg ofmethylphenidate hydrochloride, wherein the dosage form providesefficacious treatment of ADHD for about 16 hours after a single oraladministration, and wherein the dosage form has an in vitromethylphenidate hydrochloride dissolution rate that does not increase inthe presence of 5% or 20% ethanol when measured under in vitroconditions with stirring at 100 rpm at pH 1.2 for 2 hours in 900 mL of amedium comprising up to about either 5% or 20% v/v ethanol.
 17. Themethod of claim 16, wherein not more than 20% of the methylphenidatehydrochloride in the dosage form is released after two hours whenmeasured under in vitro conditions with stirring at 100 rpm at pH 1.2for 2 hours in 900 mL of a medium comprising up to about 20% v/vethanol.
 18. The method of claim 16, wherein not more than 20% of themethylphenidate hydrochloride in the dosage form is released after twohours when measured under in vitro conditions with stirring at 100 rpmat pH 1.2 for 2 hours in 900 mL of a medium comprising up to about 5%v/v ethanol.
 19. The method of claim 16, wherein the dosage formcomprises an immediate release methylphenidate hydrochloride componentand a controlled/delayed release methylphenidate hydrochloridecomponent, wherein the immediate release methylphenidate component andthe controlled/delayed release methylphenidate component, together,provide 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidatehydrochloride.
 20. The method of claim 19, wherein the dosage form hasthe following in vitro methylphenidate dissolution profile: Time (hours)Methylphenidate (% dissolved) 1 NLT 15% 4 18-38% 8 35-55% 12 68-98  16NLT 68

when tested according to the USP paddle dosage form, 100 rpm, at 37° C.;(i) starting with 900 ml simulated gastric fluid for 2 hours, (ii)followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) forthe 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP<711>Acceptance Table
 2. 21. The method of claim 19, wherein thecontrolled/delayed release methylphenidate hydrochloride component andthe immediate release methylphenidate component are provided via aplurality of coated beads.
 22. The method of claim 21, wherein each beadcomprises a portion of the controlled/delayed release methylphenidatehydrochloride component and a portion of the immediate releasemethylphenidate component.
 23. The method of claim 22, wherein each beadin the plurality of beads comprises a core comprising a first amount ofmethylphenidate hydrochloride corresponding to the portion of thedelayed/controlled release methylphenidate hydrochloride component. 24.The method of claim 23, wherein the core comprises a granule coated withthe first amount of methylphenidate hydrochloride or wherein the corecomprises a granule substrate in admixture with the first amount ofmethylphenidate hydrochloride.
 25. The method of claim 25, wherein thefirst amount of methylphenidate hydrochloride is coated with an innercontrolled release coating and an outer delayed release coating coatedover the inner controlled release coating.
 26. The method of claim 26,wherein a second amount of methylphenidate hydrochloride, correspondingto the portion of the immediate release methylphenidate component, iscoated over the outer delayed release coating.
 27. The method of claim27, wherein the delayed/controlled release methylphenidate hydrochloridecomponent comprises about 78 weight percent to about 82 weight percentof the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidatehydrochloride in the pharmaceutical composition.
 28. The method of claim28, wherein the inner controlled release coating is present in an amountof about 3 percent to about 16 percent by weight of each bead in theplurality of coated beads, and wherein the outer delayed release coatingis present in an amount of from about 3 percent to about 20 percent byweight of each bead in the plurality of coated beads.
 29. The method ofclaim 29, wherein the inner controlled release coating comprises ammoniomethacrylate copolymer, Type B USP/NF.
 30. The method of claim 30,wherein the outer delayed release coating comprises poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.